Imidazole derivatives

ABSTRACT

The present invention relates to imidazole derivatives of formula I 
                         
wherein R 1 , R 2 , R 3  and R 4  are described hereinbelow. These compounds can be used in the treatment or prevention of mGluR5 receptor mediated disorders. These compounds are useful, inter alia, in the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer&#39; disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

FIELD OF THE INVENTION

The present invention relates to imidazole derivatives of the general formula

wherein R¹, R², R³ and R⁴ are described hereinbelow. These compounds can be used in the treatment or prevention of mGluR5 receptor mediated disorders. These compounds are useful, inter alia, in the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer' disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I; mGluR2 and mGluR3 belong to group II; and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.

Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)).

Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.

SUMMARY OF THE INVENTION

The invention relates to a compound of formula I

-   wherein -   R¹ is halogen or cyano; -   R² is lower alkyl; -   R³ is selected from     -   aryl,     -   aryl substituted by one, two or three substituents, selected         from the         -   group consisting of             -   halogen,             -   lower alkyl,             -   cycloalkyl,             -   lower alkyl-halogen,             -   cyano,             -   lower alkoxy,             -   NR′R″,             -   1-morpholinyl,             -   1-pyrrolidinyl,             -   1-pyrrolidinyl substituted by OR or CH₂OR,             -   piperidinyl,             -   piperidinyl substituted by OR or CH₂OR,             -   1,1-dioxo-thiomorpholinyl,             -   piperazinyl, and             -   piperazinyl substituted by a substituent selected from                 lower alkyl, cycloalkyl and CH₂-cycloalkyl,     -   heteroaryl, and     -   heteroaryl substituted by one, two or three substituents,         selected from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano,         -   lower alkoxy,         -   NR′R″,         -   1-morpholinyl,         -   1-pyrrolidinyl,         -   1-pyrrolidinyl substituted by OR or CH₂OR,         -   piperidinyl,         -   piperidinyl substituted by OR or CH₂OR,         -   1,1-dioxo-thiomorpholinyl,         -   piperazinyl, and         -   piperazinyl substituted by a substituent selected from lower         -   alkyl, cycloalkyl and CH₂-cycloalkyl; -   R is selected from the group consisting hydrogen, lower alkyl,     cycloalkyl and CH₂-cycloalkyl; -   R′ and R″ are each independently selected from the group hydrogen,     lower alkyl, cycloalkyl, CH₂-cycloalkyl, and (CH₂)_(n)OR, wherein n     is 1 or 2; and -   R⁴ is selected from the group consisting of hydrogen, C(O)H, and     CH₂R⁵ wherein R⁵ is selected from the group consisting of hydrogen,     OH, C₁-C₆-alkyl and C₃-C₁₂-cyclo alkyl; -   or a pharmaceutically acceptable salt thereof.

Another embodiment of this invention is related to a process for preparing a compound according to general formula I following the general procedures as outlined above for compounds of formula I. Yet another embodiment is related to a pharmaceutical composition containing one or more compounds of the present invention and pharmaceutically acceptable excipients for the treatment and prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, in particular anxiety and chronic or acute pain. Yet another embodiment of this invention is related to a method of treatment and prevention of mGluR5 receptor mediated disorders as outlined above.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

The term “lower alkyl” used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and the like.

The term “lower alkoxy” denotes a lower alkyl residue in the sense of the foregoing definition bound via an oxygen atom. Examples of “lower alkoxy” residues include methoxy, ethoxy, isopropoxy and the like.

The term “halogen” denotes fluorine, chlorine, bromine and iodine.

“Aryl” represents an aromatic carbocyclic group consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature. Preferred aryl group is phenyl.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. Preferred are those heteroaryl groups selected from nitrogen. Examples of such heteroaryl groups are pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

The term “cycloalkyl” denotes a saturated carbocyclic group, containing 3-12 carbon atoms, preferably 3-6 carbon atoms.

The term “pharmaceutically acceptable salt” refers to any salt derived from an inorganic or organic acid or base.

One embodiment of the present invention is related to a compound of formula I

-   wherein -   R¹ is halogen or cyano; -   R² is lower alkyl; -   R³ is selected from     -   aryl,     -   aryl substituted by one, two or three substituents, selected         from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano,         -   lower alkoxy,         -   NR′R″,         -   1-morpholinyl,         -   1-pyrrolidinyl,         -   1-pyrrolidinyl substituted by OR or CH₂OR,         -   piperidinyl,         -   piperidinyl substituted by OR or CH₂OR,         -   1,1-dioxo-thiomorpholinyl,         -   piperazinyl, and         -   piperazinyl substituted by a substituent selected from lower             alkyl, cycloalkyl and CH₂-cycloalkyl,     -   heteroaryl, and     -   heteroaryl substituted by one, two or three substituents,         selected from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano,         -   lower alkoxy,         -   NR′R″,         -   1-morpholinyl,         -   1-pyrrolidinyl,         -   1-pyrrolidinyl substituted by OR or CH₂OR,         -   piperidinyl,         -   piperidinyl substituted by OR or CH₂OR,         -   1,1-dioxo-thiomorpholinyl,         -   piperazinyl, and         -   piperazinyl substituted by a substituent selected from lower         -   alkyl, cycloalkyl and CH₂-cycloalkyl; -   R is selected from the group consisting hydrogen, lower alkyl,     cycloalkyl and CH₂-cycloalkyl; -   R′ and R″ are each independently selected from the group hydrogen,     lower alkyl, cycloalkyl, CH₂-cycloalkyl, and (CH₂)_(n)OR, wherein n     is 1 or 2; and -   R⁴ is selected from the group consisting of hydrogen, C(O)H, and     CH₂R⁵ wherein R⁵ is selected from the group consisting of hydrogen,     OH, C₁-C₆-alkyl and C₃-C₁₂-cycloalkyl; -   or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is related to a compound of formula I

-   wherein -   R¹ is halogen; -   R² is lower alkyl; -   R³ is selected from     -   aryl substituted by one, two or three substituents, selected         from the     -   group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   cyano, and         -   lower alkoxy,     -   heteroaryl, and     -   heteroaryl substituted by one, two or three substituents,         selected from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano, and         -   lower alkoxy; and -   R⁴ is selected from hydrogen and C₁-C₆-alkyl; -   or a pharmaceutically acceptable salt thereof.

Encompassed in formula I is another embodiment, which is the compound of formula IA:

-   wherein -   R¹ is halogen; -   R² is lower alkyl; -   R³ is selected from the group consisting of     -   aryl,     -   aryl substituted by one, two or three substituents, selected         from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano,         -   lower alkoxy,         -   NR′R″,         -   1-morpholinyl,         -   1-pyrrolidinyl,         -   1-pyrrolidinyl substituted by OR or CH₂OR,         -   piperidinyl,         -   piperidinyl substituted by OR or CH₂OR,         -   1,1-dioxo-thiomorpholinyl,         -   piperazinyl, and         -   piperazinyl substituted by a substituent selected from lower         -   alkyl, cycloalkyl and CH₂-cycloalkyl     -   heteroaryl, and     -   heteroaryl substituted by one, two or three substituents         selected from the group consisting of         -   halogen,         -   lower alkyl,         -   lower alkyl-halogen,         -   cyano,         -   NR′R″,         -   1-morpholinyl,         -   1-pyrrolidinyl,         -   1-pyrrolidinyl substituted by OR or CH₂OR,         -   piperidinyl,         -   piperidinyl substituted by OR or CH₂OR,         -   1,1-dioxo-thiomorpholinyl,         -   piperazinyl, and         -   piperazinyl substituted by a substituent selected from the             group consisting of lower alkyl, cycloalkyl and             CH₂-cycloalkyl; -   R is selected from the group consisting of hydrogen, lower alkyl,     cycloalkyl and CH₂-cycloalkyl; and -   R′ and R″ are each independently selected from the group consisting     of hydrogen, lower alkyl, cycloalkyl, CH₂-cycloalkyl and     (CH₂)_(n)OR, where n is 1 or 2; -   or a pharmaceutically acceptable salt thereof.

Yet another embodiment of this invention is directed to a compound of formula IA

-   wherein -   R¹ is halogen; -   R² is lower alkyl; and -   R³ is selected from     -   aryl substituted by one, two or three substituents, selected         from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   cyano, and         -   lower alkoxy,     -   heteroaryl, and     -   heteroaryl substituted by one, two or three substituents,         selected from the group consisting of         -   halogen,         -   lower alkyl,         -   cycloalkyl,         -   lower alkyl-halogen,         -   cyano, and         -   lower alkoxy; -   or a pharmaceutically acceptable salt thereof.

One embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is aryl substituted by one or two halogen; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two lower alkyl-halogen; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two halogen; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is aryl substituted by one or two substituents selected from halogen and lower alkyl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is aryl substituted by one or two lower alkyl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is aryl substituted by one or two lower alkoxy; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is aryl substituted by one or two cyano; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ heteroaryl substituted by one or two lower alkyl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two lower alkoxy; and R⁴ is selected from hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is cyano; R² is lower alkyl; R³ is aryl substituted by one or two halogen; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two substituents selected from halogen and lower alkyl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is cyano; R² is lower alkyl; R³ is heteroaryl substituted by one or two halogen; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two cycloalkyl; and R⁴ is hydrogen.

Another embodiment of the compound of formula I in the present invention is where R¹ is halogen; R² is lower alkyl; R³ is heteroaryl substituted by one or two substituents selected from lower alkyl-halogen and alkyl; and R⁴ is hydrogen.

Preferred compounds of formula I and IA are those, in which R¹ is chloro or fluoro.

Especially preferred are those compounds from this group, in which R³ is unsubstituted or substituted heteroaryl, wherein the substitution is selected from fluoro, CF₃ and lower alkyl, for example the following compounds:

-   2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-trifluoromethyl-pyrimidine, -   2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyrazine, -   2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-6-trifluoromethyl-pyridine, -   3-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-5-fluoro-pyridine, -   4-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazolyl-1-yl]-2-trifluoromethyl-pyrimidine, -   2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazolyl-1-yl]-6-methyl-4-trifluoromethyl-pyridine     and -   2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazoly-1-yl]-5-methyl-pyridine.

Especially preferred are further those compounds of this group, wherein R³ is aryl, substituted by one or more halogen, for example the following compounds:

-   2-Chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, -   2-Fluoro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, -   2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, -   2-Chloro-4-[1-(3,5-difluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine,     and -   2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

The compounds of formula I or IA of the invention may be prepared according to a process

which comprises reacting a compound of formula II

wherein R¹, R² and R⁴ have the meanings as defined above, with a compound of formula III R³—Z  (III) wherein R³ has the meanings as defined above and Z is halogen or B(OH)₂.

The reaction as described in (a) may be carried out in accordance with standard procedures, e.g. by arylation of a compound of formula II using an aromatic boronic acid and a copper catalyst in a solvent like dichloromethane or tetrahydrofurane [see e.g. Colmann et al., Org. Lett. 2:1233 (2000)] or by heating a compound of formula II and a compound of formula III wherein Z is halogen with a base like potassium carbonate or cesium carbonate in a solvent like dimethylformamide, or Pd catalyzed according to Buchwald conditions [see e.g. Example 8; Buchwald et al., Tetrahedron Lett. 40:2657 (1999)].

In another embodiment, the compounds of formula I or IA of the invention may be prepared according to a process which comprises reacting a compound of formula IV

wherein R², R³ and R⁴ have the meanings as defined above, with a compound of formula V

wherein R¹ has the meanings as defined above and X is halogen.

The reaction as described in (b) may be carried out by a Sonogashira coupling of a compound of formula IV and a compound of formula V in the presence of, e.g., CuI, (Ph₃P)₂PdCl₂, Et₃N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)]. In one embodiment the meaning X in compounds of formula V is bromine or iodine.

In yet another embodiment, the compounds of formula I or IA of the invention may be prepared according to a process which comprises reacting a compound of formula VI

wherein R², R³ and R⁴ have the meanings as defined above and hal is halogen, with a compound of formula VII

wherein R¹ has the meaning as defined above and Y is trimethylsilyl or hydrogen.

The reaction described above may, e.g. be carried out in the presence of CuI, (Ph₃P)₂PdCl₂, Et₃N, n-Bu₄F in a solvent like tetrahydrofuran or dimethylformamide.

If desired, the above compounds obtained may be converted into their pharmaceutically acceptable salts.

The salt forms are made by standard procedures known to the skilled artisan.

The compounds of formulae II, IV, VI and VII are novel and also an embodiment of the present invention.

The compounds of formulae III and V are commercially available or their preparation is known to the skilled artisan.

The compounds of formula II may be prepared by reacting a compound of formula VIII

wherein R² and R⁴ have the above meanings and hal is halogen, with a compound of formula VII as above.

The compounds of formula VIII may be prepared as described e.g. in Cliff and Pyne [Synthesis 681-682 (1994)].

The compounds of formula IV may be prepared by reacting a compound of formula IX

wherein R², R³ and R⁴ have the meanings as defined above, with dimethyl (1-diazo-2-oxopropyl)phosphonate as described in Ohira [Synth. Comm. 19:561-564 (1989)].

Compounds of formula VI may be prepared by reacting a compound of formula VIII as above with a compound of formula X R³—Z  (X) wherein R³ has the meanings as defined above and Z is halogen or B(OH)₂.

The reaction may take place by arylation of a compound of formula VIII either by using an aromatic boronic acid (compound of formula X) and a copper catalyst in a solvent like dichloromethane or tetrahydrofurane under an oxygen atmosphere [see e.g. Colmann et al., Org. Lett. 2:1233 (2000)] or by heating with R³—Z when Z is halogen with a base like potassium carbonate or cesium carbonate in a solvent like dimethylformamide, or Pd catalyzed according to Buchwald conditions [see e.g. Example 8; Buchwald et al., Tetrahedron Lett. 40:2657 (1999)].

Compounds of formula VII may be prepared by reacting a compound of formula V as above with a compound of formula XI

The reaction may take place by a Sonogashira coupling in the presence of eg. CuI, (Ph₃P)₂PdCl₂, Et₃N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)].

Compounds of formula IX may be prepared by oxidizing a compound of formula XII

according to methods known to the skilled artisan.

Compounds of formula XII may be prepared by deprotecting a compound of formula XIII

according to methods known to the skilled artisan.

Compounds of formula XIII may be prepared by alkylating a compound of formula XIV

with an alkylating agent of formula XVa R²-hal  (XVa) according to methods known to the skilled artisan. Starting compounds of formula XVa are commercially available.

Compounds of formula XIV may be prepared by treating a compound of formula XV

with tert.-butyl dimethyl silyl chloride according to methods known to the skilled artisan.

Compounds of formula XV may be prepared by treating a compound of formula

with a reducing agent according to methods known to the skilled artisan.

Compounds of formula XVI may be prepared by hydrolyzing a compound of formula XVII

according to methods known to the skilled artisan.

Compounds of formula XVII may be prepared by treating a compound of formula XVIII R³—NH₂  (XVIII) with e.g. triethyl orthoformate, ethylnitro acetate, glacial acetic acid and iron powder according to methods known to the skilled artisan.

Compounds of formula XVIII are commercially available.

The compounds of general formula IA, I and their pharmaceutically acceptable salts can also be manufactured by two general procedures, which procedures are outlined below in scheme 1 for compounds wherein R¹ is chloro, R² is methyl and R³ is 4-trifluoromethyl-pyrimidine-2-yl (see example 3), and in scheme 2 for compounds, wherein R¹ is chloro, R² is methyl and R³ is 4-fluoro-phenyl (see example 1), but which procedures are applicable for all compounds according to formula I and IA, as described below:

a) reacting a compound of formula

with a compound of formula R³Z III wherein R₃ has the meanings as defined above and Z is halogen or B(OH)₂, to a compound of formula

wherein R¹, R² and R³ are as described above and hal is halogen, preferably chloro or fluoro, or b) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein R¹, R² and R³ are as described above, and if desired, when R⁴ is other than hydrogen, c) reacting the compound of formula IA with a compound of formula: R⁴Hal  VI to a compound of formula

wherein R¹, R², R³ and R⁴ are as described above, and if desired, converting the compounds obtained into pharmaceutically acceptable salts.

Procedure 1 is summarized in scheme 1.

The starting materials are known compounds or may be prepared according to methods known in the art.

Step 1:

2-Chloro-4-iodo-pyridine is dissolved in THF and triethyl amine. Then oxygen is removed from the solution. Triphenylphosphine and bis(triphenylphosphine)palladium(II)chloride are added and the reaction mixture is stirred at room temperature for about 1 h. Copper(I)iodide and trimethylsilylacetylen are added. The reaction mixture is stirred at room temperature overnight. The desired product 2-chloro-4-trimethylsilanylethynyl-pyridine is obtained after conventional work-up. This material was used without any further purification for the next step.

Step 2:

Solution 1: 2-Chloro-4-trimethylsilanylethynyl-pyridine and 5-iodo-2-methyl-1H-imidazole, (synthesis: M. D. Cliff, S. G. Pyne, Synthesis 1994, 681-682) are dissolved in THF and DMF. Then oxygen is removed from the solution.

Solution 2: Triphenylphosphine, bis(triphenylphosphine)-palladium(II)chloride, copper(I)iodide and triethyl amine are dissolved in THF. Then oxygen is removed from the solution.

Solution 2 is heated to 40° C. and solution 1 is added dropwise. The reaction mixture is heated to about 60° C. and tetrabutylammonium fluoride solution is added dropwise. The reaction is then stirred at room temperature overnight. The desired product 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine is obtained after conventional work-up.

Step 3:

2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine is dissolved in dimethyl formamide. Potassium carbonate and 2-chloro-4-trifluoromethyl-pyrimidine are added and the reaction mixture is stirred at about 80° C. overnight. It is obtained 2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-trifluoromethyl-pyrimidine.

Procedure 2 is summarized in scheme 2.

Step 1:

4-Fluoroaniline is mixed at room temperature with triethyl orthoformate, ethylnitro acetate and glacial acetic acid. The reaction mixture is refluxed with mechanical stirring for about 2 h. More triethyl orthoformate and glacial acetic acid are added. Iron powder is added in 3 portions during about 8 h while maintaining the reaction mixture at reflux. Ethyl acetate is added and reflux is continued. The crude product 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester is used without any further purification for the next step.

Step 2:

Crude 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester is dissolved in dioxane and sodium hydroxide solution. The reaction mixture is refluxed for about 2 h. Charcoal is added and reflux is continued. The desired compound I-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid is obtained.

Step 3:

1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid is dissolved in THF. Borane tetrahydrofuran complex in THF is added dropwise. The reaction is refluxed for 2 h and stirred at room temperature overnight. The reaction mixture is then cooled to 0° C. and methanol is added dropwise. The solvents are evaporated and the residue is taken up in HCl and refluxed for 2 h. The reaction mixture is then cooled to 0° C. and sodium hydroxide solution is added dropwise. The desired compound [1-(4-fluoro-phenyl)-1H-imidazol-4-yl]-methanol is obtained.

Step 4:

[1-(4-Fluoro-phenyl)-1H-imidazol-4-yl]-methanol is dissolved in DMF. Imidazole and tert. butyldimethyl chlorosilane are added. The reaction mixture is stirred at about 45° C. overnight. The desired compound 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole is obtained.

Step 5:

4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole is dissolved in THF and cooled to −78° C. n-Butyl lithium in hexane is added dropwise. The reaction mixture is warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane is added dropwise. The reaction mixture is slowly warmed up to room temperature and stirred at room temperature overnight. The desired compound 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.

Step 6:

4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is dissolved in THF. Tetrabutyl ammoniumfluoride in THF is added and the reaction mixture is stirred at room temperature overnight. The desired compound [1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol is obtained.

Step 7:

[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol is dissolved in methylene chloride. Mangan (IV) oxide is added and the reaction mixture is stirred at room temperature for 3 days. The suspension is filtered through a dicalite speed plus pad and the desired compound (4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde is obtained.

Step 8:

Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester is dissolved in methanol. Potassium carbonate is added. A solution of 1-(4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde in methanol is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight. The desired compound 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.

Step 9:

2-Chloro-4-iodopyridine is dissolved in THF. This mixture is evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine and bis(triphenylphosphine)palladium(II)chloride are added and the reaction mixture is stirred at room temperature for 1 h. Copper(I)iodide and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole are added. The reaction mixture is stirred at room temperature for 3 days. The desired product 2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1 H-imidazol-4-ylethynyl]-pyridine is obtained.

Pharmaceutically acceptable salts of compounds of formula I can be manufactured readily according to methods known in the art and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.

The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain. Treatable neurological disorders are for instance epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, ethanol addiction, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia.

The compounds of formula I and their pharmaceutically acceptable salts are especially useful as analgesics. Treatable kinds of pain include inflammatory pain such as arthritis and rheumatoid disease, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain, post-operative pain and pain associated with various conditions like cancer, angina, renal or billiay colic, menstruation, migraine and gout.

The pharmacological activity of the compounds was tested using the following method:

For binding experiments, cDNA encoding human mGlu 5a receptor was transiently transfected into EBNA cells using a procedure described by Schlaeger and Christensen [Cytotechnology 15:1-13 (1998)]. Cell membrane homogenates were stored at −80° C. until the day of assay where upon they were thawed and resuspended and polytronised in 15 mM Tris-HCl, 120 mM NaCl, 100 mM KCl, 25 mM CaCl₂, 25 mM MgCl₂ binding buffer at pH 7.4 to a final assay concentration of 20 μg protein/well.

Saturation isotherms were determined by addition of twelve [³H]MPEP concentrations (0.04-100 nM) to these membranes (in a total volume of 200 μl) for 1 h at 4° C. Competition experiments were performed with a fixed concentration of [³H]MPEP (2 nM) and IC₅₀ values of test compounds evaluated using 11 concentrations (0.3-10,000 nM). Incubations were performed for 1 h at 4° C.

At the end of the incubation, membranes were filtered onto unifilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.1% PEI in wash buffer, Packard BioScience, Meriden, Conn.) with a Filtermate 96 harvester (Packard BioScience) and washed 3 times with cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 μM MPEP. The radioactivity on the filter was counted (3 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 μl of microscint 40 (Can berra Packard S. A., Zürich, Switzerland) and shaking for 20 min. For functional assays, [Ca²⁺]i measurements were performed as described previously by Porter et al. [Br. J. Pharmacol. 128:13-20 (1999)] on recombinant human mGlu 5a receptors in HEK-293 cells. The cells were dye loaded using Fluo 4-AM (obtainable by FLUKA, 0.2 μM final concentration). [Ca²⁺]i measurements were performed using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA). Antagonist evaluation was performed following a 5 min preincubation with the test compounds followed by the addition of a submaximal addition of agonist.

The inhibition (antagonists) curves were fitted with a four parameter logistic equation giving IC₅₀, and Hill coefficient using an iterative non linear curve fitting software (Xcel fit).

For binding experiments the Ki values of the compounds tested are given. The Ki value is defined by the following formula: K _(i) =IC ₅₀/[1+L/K _(d)] in which the IC₅₀ values are those concentrations of the compounds tested which cause 50% inhibition of the competing radioligand ([³H]MPEP). L is the concentration of radioligand used in the binding experiment and the K_(d) value of the radioligand is empirically determined for each batch of membranes prepared.

The compounds of the present invention are mGluR 5a receptor antagonists. The activities of compounds of formula I as measured in the assay described above are in the range of K_(i)<70 nM.

Example Ki (nM) 2 23 5 21 6 63 8 24 10 44 18 25 20 15 22 26 25 40 26 12 28 23 30 36 31 69 33 24 35 39

The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such as carriers for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula I or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

The following examples are provided to further elucidate the invention:

EXAMPLE 1 2-Chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II)chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0→10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H⁺).

EXAMPLE 2 2-Fluoro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=296.1 (M+H⁺), was prepared in accordance with the general method of example 1 from 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole and 2-fluoro-4-iodopyridine.

EXAMPLE 3 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-trifluoromethyl-pyrimidine

2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (190 mg, 1.37 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (189 mg, 0.66 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diethyl ether and the desired compound was obtained as a white solid (190 mg, 76%), MS: m/e=364.1 (M+H⁺).

EXAMPLE 4 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyrazine

The title compound, MS: m/e=296.1 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloropyrazine.

EXAMPLE 5 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-6-trifluoromethyl-pyridine

The title compound, MS: m/e=363.1.1 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-(trifluoromethyl)pyridine.

EXAMPLE 6 3-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-5-fluoro-pyridine

The title compound, MS: m/e=313.1 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluoro-pyridine.

EXAMPLE 7 2-Chloro-4-[1-(4-chloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 30 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-chlorobenzene boronic acid (216 mg, 1.38 mmol) and [Cu(OH)TMEDA]₂Cl₂ (113 mg, 0.24 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→3:2 gradient) and by recrystallization from diisopropylether. The desired compound was obtained as a white solid (42 mg, 19%), MS: m/e=329.2 (M+H⁺).

EXAMPLE 8 2-Chloro-4-[1-(3,4-dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=363.7 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,4-dichlorobenzene boronic acid.

EXAMPLE 9 2-Chloro-4-[1-(4-fluoro-phenyl)-2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine fumarate Step 1: 1-(4-Fluoro-phenyl)-4-iodo-2-isopropyl-1H-imidazole

The title compound, MS: m/e=331.1 (M+H⁺), was prepared in accordance with the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-fluorobenzene boronic acid.

Step 2: 2-Chloro-4-[1-(4-fluoro-phenyl)-2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine fumarate

The title compound, MS: m/e=340.1 (M+H⁺), was prepared in accordance with the general method of example B, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 1-(4-fluoro-phenyl)-4-iodo-2-isopropyl-1H-imidazole and crystallization from methanol and 1.05 eq fumaric acid.

EXAMPLE 10 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine-2-carbonitrile

The title compound, MS: m/e=303.1 (M+H⁺), was prepared in accordance with the general method of example 7 from 4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 4-fluorobenzene boronic acid.

4-(2-Methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile

Triphenylphosphine (126 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II)chloride (1.01 g, 1.44 mmol) and triethylamine (3.65 g, 101.2 mmol) were dissolved in 40 ml of dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. 4-iodo-2-methyl-1H-imidazole [Tetrahedron Letters 30(11), 1409 (1989)] (5.0 g, 20.8 mmol), 4-trimethylsilanylethynyl-pyridine-2-carbonitrile (4.43 g, 22.1 mmol) and copper (I) iodide (46 mg, 0.24 mmol) were added and the mixture was warmed to 60° C. A 1M solution of tetrabutylammonium fluoride (24 ml, 24.0 mmol) was added dropwise over a period of 30 min. After the addition was finished, the reaction mixture was stirred at 60° C. for another hour. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (methanol/methylene chloride 5:95). The desired product was obtained as a light yellow solid (1.06 g, 21%). MS: m/e=208.9 (M⁺).

4-Trimethylsilanylethynyl-pyridine-2-carbonitrile

4-Bromo-2-pyridinecarbonitrile [Cesko-Slovenska Farmacie 25(5),181 (1976)] (0.73 g, 4.0 mmol) was dissolved in 18 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (31 mg, 0.12 mmol) and bis(triphenylphosphine)palladium(II) chloride (141 mg, 0.20 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (23 mg, 0.12 mmol) and trimethylsilyl-acetylene (590 mg, 6.0 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with 100 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/methylene chloride 1:2). The desired product was obtained as a yellow oil (329 mg, 41%), MS: m/e=201.3 (M+H⁺).

EXAMPLE 11 2-Chloro-4-[1-(2,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=330.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,4-difluorobenzene boronic acid.

EXAMPLE 12 2-Chloro-4-[1-(3,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=330.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1 H-imidazol-4-ylethynyl)-pyridine and 3,4-difluorobenzene boronic acid.

EXAMPLE 13 4-[1-(3,4-Difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine-2-carbonitrile

The title compound, MS: m/e=321.5 (M+H⁺), was prepared in accordance with the general method of example 7 from 4-(2-Methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 3,4-fluorobenzene boronic acid.

EXAMPLE 14 2-Chloro-4-[1-(3-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=312.5 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-fluorobenzene boronic acid.

EXAMPLE 15 2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=330.3 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluorobenzene boronic acid.

EXAMPLE 16 4-[1-(3,5-Difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine-2-carbonitrile

The title compound, MS: m/e=321.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 3,5-fluorobenzene boronic acid.

EXAMPLE 17 2-Chloro-4-[1-(3-fluoro-4-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=326.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-fluoro-4-methyl-benzene boronic acid.

EXAMPLE 18 2-Chloro-4-[1-(4-fluoro-3-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=326.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-fluoro-3-methyl-benzene boronic acid.

EXAMPLE 19 2-Chloro-4-[1-(3-chloro-4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=347.2 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-chloro-4-fluoro-benzene boronic acid.

EXAMPLE 20 2-Chloro-4-[1-(4-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=308.8 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methyl-benzene boronic acid.

EXAMPLE 21 2-Chloro-4-[1-(3-methoxy-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=324.8 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-methoxy-benzene boronic acid.

EXAMPLE 22 2-Chloro-4-[1-(4-methoxy-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=324.8 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methoxy-benzene boronic acid.

EXAMPLE 23 3-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-benzonitrile

The title compound, MS: m/e=319.8 (M+H⁺), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-cyano-benzene boronic acid.

EXAMPLE 24 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyrimidine

The title compound, MS: m/e=296.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-pyrimidine.

EXAMPLE 25 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-methyl-pyrimidine

The title compound, MS: m/e=310.4 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-4-methyl-pyrimidine.

EXAMPLE 26 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-methoxy-pyrimidine

The title compound, MS: m/e=326.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-4-methoxy-pyrimidine.

EXAMPLE 27 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-5-fluoro-pyrimidine

The title compound, MS: m/e=314.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-fluoro-pyrimidine.

EXAMPLE 28 4-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-2-trifluoromethyl-pyrimidine

The title compound, MS: m/e=364.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-chloro-2-trifluoromethyl-pyrimidine.

EXAMPLE 29 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-6-methyl-pyridine

The title compound, MS: m/e=309.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-methyl-pyridine.

EXAMPLE 30 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-5-methyl-pyridine

The title compound, MS: m/e=309.5 (M+H⁺), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-5-methyl-pyridine.

EXAMPLE 31 4-[1-(6-Chloro-pyridin-3-yl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine-2-carbonitrile

The title compound, MS: m/e=320.0, 322.1 (M+H⁺), was prepared in accordance with the general method of example 7 from 4-(2-Methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 6-chloro-3-pyridinyl-boronic acid.

EXAMPLE 32 2-Chloro-4-[1-(6-chloro-pyridin-3-yl)-2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine Step 1: 2-Chloro-5-(4-iodo-2-isopropyl-imidazol-1-yl)-pyridine

The title compound, MS: m/e=348.4 (M+H⁺), was prepared in accordance with the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-chloropyridine-5-boronic acid.

Step 2: 2-Chloro-4-[1-(6-chloro-pyridin-3-yl)-2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=358.1 (M+H⁺), was prepared in accordance with the general method of example B, step 2, from 2-Chloro-4-trimethylsilanylethynyl-pyridine and 2-Chloro-5-(4-iodo-2-isopropyl-imidazol-1-yl)-pyridine.

EXAMPLE 33 5-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-2-cyclopropyl-pyridine Step 1: 2-Chloro-5-(4-iodo-2-methyl-imidazol-1-yl)-pyridine

The title compound, MS: m/e=320.2 (M+H⁺), was prepared in accordance with the general method of example 7 from 4-iodo-2-methyl-1H-imidazole and 4-chloropyridine-5-boronic acid.

Step 2: 2-Chloro-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl))-pyridine

The title compound, MS: m/e=290.6 (M+H⁺), was prepared in accordance with the general method of example B, step 1, from 2-chloro-5-(4-iodo-2-methyl-imidazol-1-yl)-pyridine and trimethylsilylacetylen.

Step 3: 2-Cyclopropyl-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine

2-Chloro-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine (425 mg, 1.47 mmol) were dissolved in 0.4M cyclopropylzinc chloride in THF (7.33 mL, 0.4M in THF) and tetrakis(triphenylphosphin)palladium (34 mg, 0.03 mmol) were added. The reaction mixture was refluxed for 16 hrs and poured into 50 mL sat. sodium bicarbonate solution. The mixture and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→1:1 gradient) and the desired product was obtained as a light yellow solid (395 mg, 91%), MS: m/e=296.2 (M+H⁺).

Step 4: 2-Chloro-4-[1-(6-cyclopropyl-pyridin-3-yl)-2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=335.6 (M+H⁺), was prepared in accordance with the general method of example B, step 2, from 2-cyclopropyl-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine and 2-chloro-4-iodo-pyridine.

EXAMPLE 34 2-Chloro-4-[1-(3,5-difluoro-4-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine

2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.45 ml, 0.91 mmol) was added and the mixture stirred for 15 min at −75° C. Iodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO₃— solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=344.5 (M+H⁺).

EXAMPLE 35 2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine

The title compound, MS: m/e=326.5 (M+H⁺), was prepared in accordance with the general method of example 34 from 2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine.

EXAMPLE 36 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazolyl-1-yl]-6-methyl-4-trifluoromethyl-pyridine Step 1: 2-2-(4-Iodo-2-methyl-imidazol-1-yl)-6-methyl-4-trifluoromethyl-pyridine

The title compound, MS: m/e=368.0 (M+H⁺), was prepared in accordance with the general method of example 3 from 5-iodo-2-methyl-1H-imidazole and 2-chloro-6-methyl-4-(trifluoromethyl)-pyridine.

Step 2: 2-[4-(2-Chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-6-methyl-4-trifluoromethyl-pyridine

The title compound, MS: m/e=377.2 (M+H⁺), was prepared in accordance with the general method of example B, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 2-2-(4-Iodo-2-methyl-imidazol-1-yl)-6-methyl-4-trifluoromethyl-pyridine.

SYNTHESIS OF INTERMEDIATES Example A 4-Ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole

Step 1: 1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester

4-Fluoroaniline (20.0 g, 175 mmol) was mixed at room temperature with triethyl orthoformate (35.4 g, 233 mmol), ethylnitro acetate (28.5 g, 210 mmol) and 4 mL glacial acetic acid. The reaction mixture was refluxed with mechanical stirring for 2 h. More triethyl orthoformate (200 mL) and glacial acetic acid (200 mL) were added. Iron powder (100 g, 1.79 mol) was added in 3 portions during 8 h while maintaining the reaction mixture at reflux. Ethyl acetate (700 mL) was added and reflux was continued for another 2 h. The reaction mixture was filtered through a dicalite speed plus pad and washed with 500 mL ethyl acetate. The solvents were evaporated and the crude product was used without any further purification for the next step.

Step 2: 1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid

Crude 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (175 mmol) was dissolved in 450 mL dioxane and 450 mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2 h. Charcoal (1 g, Norit SA II) was added and reflux was continued for another 20 min. The mixture was filtered hot and washed with 50 mL 2N sodium hydroxide solution. The filtrate was treated with 550 mL 2N HCl and stirred at room temperature overnight. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as an off-white solid (28 g, 78%), MS: m/e 205.1 (M−H).

Step 3: [1-(4-Fluoro-phenyl)-1H-imidazol-4-yl]-methanol

1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THF, 174 mmol) was added dropwise. The reaction was refluxed for 2 h and stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and 100 mL methanol were added dropwise. The solvents were evaporated. The residue was taken up in 100 mL 2N HCl and refluxed for 2 h. The reaction mixture was then cooled to 0° C. and 120 mL 2N sodium hydroxide solution were added dropwise. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as a white solid (13 g, 78%), MS: m/e=193.2 (M+H)⁺.

Step 4: 4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole

[1-(4-Fluoro-phenyl)-1H-imidazol-4-yl]-methanol (13 g, 67.5 mmol) was dissolved 65 mL DMF. Imidazole (11 g, 162 mmol) and tert. butyldimethyl chlorosilane (12.2 g, 81 mmol) were added. The reaction mixture was stirred at 45° C. overnight and poured into 500 mL water. The aqueous phase was extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (methylene chloride/methanol 98:2) and the desired compound was obtained as a light brown oil (20 g, 96%), MS: m/e=291.2 (M-CH₃), m/e=249.1 (M-tert. butyl).

Step 5: 4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole

4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole (18.2 g, 59.2 mmol) was dissolved in 600 mL dry THF and cooled to −78° C. n-Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane (7.4 mL, 11.8 mmol) was added dropwise. The reaction mixture was slowly warmed up to room temperature and stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 50:50→20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%), MS: m/e=321.1 (M+H⁺).

Step 6: [1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol

4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL, 1M in THF, 91 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was suspended in 150 mL ethyl acetate, filtered and dried. The desired compound was obtained as a white solid (7.16 g, 76%), MS: m/e=207.1 (M+H⁺).

Step 7: 1-(4-Fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde

[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol (7.16 g, 34.7 mmol) was dissolved in 2.3 L methylene chloride. Mangan (IV) oxid (26.8 g, 278 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1 L methylene chloride. The solvents were evaporated and the desired compound was obtained as a white solid (5.87 g, 83%), MS: m/e=205.1 (M+H⁺).

Step 8: 4-Ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole

Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (6.51 g, 33.9 mmol) was dissolved in 100 mL methanol. Potassium carbonate (7.81 g, 56.5 mmol) was added. A solution of 1-(4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde (5.77 g, 45 mmol) in 100 mmol methanol was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→0:100 gradient) and the desired compound was obtained as a white solid (3.81 g, 67%), MS: m/e=200.1 (M⁺).

Example B 2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine

Step 1: 2-Chloro-4-trimethylsilanylethynyl-pyridine

2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.

Step 2: 2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine

Solution 1: 2-Chloro-4-trimethylsilanylethynyl-pyridine (8.9 g, purity<100% as indicated in step 1) and 5-iodo-2-methyl-1H-imidazole (13.24 g, 64 mmol, synthesis: M. D. Cliff, S. G. Pyne, Synthesis 1994, 681-682) were dissolved in 75 mL dry THF and 20 mL dry DMF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution.

Solution 2: Triphenylphosphine (223 mg, 0.85 mmol), bis(triphenylphosphine)-palladium(II)chloride (1.79 g, 2.55 mmol), copper(I)iodide (81 mg, 0.43 mmol) and triethyl amine (8.87 mL, 64 mmol) were dissolved in 75 mL dry THF. This mixture was also evacuated and backfilled with argon several times to remove oxygen from the solution Solution 2 was heated to 40° C. and solution 1 was added dropwise. The reaction mixture was heated to 60° C. and tetrabutylammonium fluoride solution (1M in THF, 55 mL, 55 mmol) was added dropwise during 45 min. The reaction was than stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (methylene chloride/methanol 95:5) and recrystallized from a mixture of methylene chloride and ethyl acetate. The desired product was obtained as a light brown solid (2.89 g, 31%).

Example C 4-Chloro-2-trifluoromethyl-pyrimidine

This compound was prepared according to S. Inoue, A. J. Saggiomo, E. A. Nodiff, J. Org. Chem. 1961, 26, 4504.

Preparation of the Pharmaceutical Compositions:

Example I

Tablets of the following composition are produced in a conventional manner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

Example II

Tablets of the following composition are produced in a conventional manner:

mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate 4 Tablet weight 400

Example III

Capsules of the following composition are produced:

mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size. 

1. A compound of formula I

wherein R¹ is chloro or fluoro; R² is lower alkyl; R³ is aryl substituted by one, two or three halogen(s); and R⁴ is selected from the group consisting of hydrogen, C(O)H, and CH₂R⁵ wherein R⁵ is selected from the group consisting of hydrogen, OH, C₁-C₆-alkyl and C₃-C₁₂-cycloalkyl; or a pharmaceutically acceptable salt thereof.
 2. A compound of formula I

in accordance with claim 1 wherein R¹ is chloro or fluoro; R² is lower alkyl; R³ is aryl substituted by one, two or three halogen(s); and R⁴ is selected from the group consisting of hydrogen and C₁-C₆-alkyl; or a pharmaceutically acceptable salt thereof.
 3. A compound of formula I

in accordance with claim 1 wherein R¹ is chloro or fluoro; R² is lower alkyl; and R³ is aryl substituted by one, two or three halogen(s); and R⁴ is hydrogen; or a pharmaceutically acceptable salt thereof.
 4. The compound of formula I in accordance with claim 2, wherein the compound is selected from 2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, 2-fluoro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, 2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine, and 2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.
 5. A pharmaceutical composition which comprises a compound of formula I in accordance with claim 1

wherein R¹ is chloro or fluoro; R² is lower alkyl; R³ is aryl substituted by one, two or three halogen(s); and R⁴ is selected from the group consisting of hydrogen, C(O)H, and CH₂R⁵ wherein R⁵ is selected from the group consisting of hydrogen, OH, C₁-C₆-alkyl and C₃-C₁₂-cycloalkyl; or a pharmaceutically acceptable salt thereof; and a pharmaceutically inert carrier. 